1-Substituted-2-imino-pyrido[2,3-d]pyrimidin-4(1H)-ones

ABSTRACT

ANTI-HISTAMINICS OF THE FORMULA: ##SPC1## 
     wherein 
     R 1  is alkyl, alkenyl or phenalkyl, 
     R 2  and R 3  are hydrogen, alkyl or alkenyl, and 
     R is an optional substituent, are prepared by reacting a 3,4-dihydro-1,3-dioxo-1H-pyrido [2,3-d][1,3]oxazine (a 3-azaisatoic anhydride) with a S-methyl-thiopseudourea.

This application is a continuation-in-part of application Ser. No.437,470, filed Jan. 28, 1974, which in turn is a continuation-in-part ofcopending application Ser. No. 373,475, filed June 25, 1973, now allabandoned.

This invention relates to 1,2-disubstituted-pyrido[2,3-d]pyrimidin-4(1H)-ones, their preparation and intermediates usefulin their preparation and to compositions and methods utilizing thepharmacological activity of said compounds.

The compounds of the invention may be represented by the structuralformula I: ##SPC2##

wherein

R₁ is alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 8 carbon atoms orphenalkyl of the formula II: ##SPC3##

n is 0 to 1,

R" is hydrogen or methyl, preferably with R" being hydrogen when n is 1,

R₂ is hydrogen, alkyl of 1 to 6 carbon atoms or alkenyl of 3 to 6 carbonatoms,

R₃ is hydrogen, alkyl of 1 to 6 carbon atoms or alkenyl of 3 to 6 carbonatoms.

R is hydrogen or alkyl of 1 to 3 carbon atoms, and

Y and Y' are independently hydrogen, halo of atomic weight of from 18 to36, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms or oneis hydrogen and the other bromo or trifluoromethyl.

The compounds of the formula (I) having the formula (Ia): ##SPC4##

In which R and R₁ are as defined, and R₂ ' and R₃ ' are the samerespectively as R₂ and R₃ as above defined but subject to the provisothat R₂ ' is a hydrocarbon when R₃ ' is a hydrocarbon may be prepared ina Step A reaction involving reacting a compound of the formula (III):##SPC5##

wherein R and R₁ are as defined, with a compound of the formula (IV):##EQU1## wherein R₂ ' and R₃ ' are as defined.

The compounds of the formula I having the formula Ib: ##SPC6##

In which R, R₁ and R₂ are as above defined and R₃ " is alkyl of 1 to 6carbon atoms or alkenyl of 3 to 6 carbon atoms may also be prepared in aStep B reaction by reacting a compound of the formula Ic: ##SPC7##

In which R and R₁ are as defined, M is hydrogen or an alkali metal,preferably sodium and R₂ " is hydrogen, alkyl of 1 to 6 carbon atoms,alkenyl of 3 to 6 carbon atoms or M as above defined, with an alkylatingagent of the formula V:

    X--R.sub.3 "                                               V

in which R₃ " is as above defined and X is halo of atomic weight of from35 to 127, preferably iodo.

The compounds of the formula I having the formula Id: ##SPC8##

In which R, R₁ and R₃ " are as defined and R₂ '" is alkyl of 1 to 6carbon atoms or alkenyl of 3 to 6 carbon atoms may also be prepared in aStep C reaction by reacting a compound of the formula Ie: ##SPC9##

in which M, R, R₁ and R₃ " are as defined, with an alkylating agent ofthe formula VI:

    X--R.sub.2 '"                                              VI

in which X and R₂ '" are as defined.

The compounds of the formula Ia, defined above, may also be prepared ina Step D reaction involving cyclizing a compound of the formula VII:##SPC10##

wherein R, R₁, R₂ ' and R₃ ' are as defined.

The preparation of compounds Ia by the reaction of Step A can be carriedout at elevated temperatures, typically in the range of at least 80°C.to 200°C., preferably 120°C. to 180°C. The reaction is convenientlycarried out in an organic solvent of conventional type providing aninert reaction medium. The higher boiling solvents for use at refluxtemperatures represent the preferred solvents, e.g., xylene andespecially diglyme and the like. The reaction is preferably carried outin the presence of a base, e.g. potassium carbonate; and when thecompound IV is employed directly in acid addition salt form, it is ofcourse desirable to employ an amount of base greater than the amountnecessary to neutralize the acid. It will be appreciated by thoseskilled in the art that the compounds of the formula IV are tautomericand have the alternative and equivalent structure represented by theformula IVA: ##EQU2## wherein R₂ ' and R₃ ' are as above defined. Itthus may be foreseen that the reaction of Step A in which R₂ ' and R₃ 'in the compounds IV (and IVA) are dissimilar alkyls and/or alkenyls maylead to mixtures of the final products of the formula Ia. Accordingly,the final products in R₂ ' and R₃ ' are dissimilar hydrocarbon groupsmay in some instances be preferably prepared by the reaction of Step Band Step C. In general, the reaction product of formula Ia may berecovered from the reaction of Step A by working up by conventionalprocedures.

The reaction of Step B is of known type and preferably effectedemploying a compound Ic in which M is an alkali metal. Such compounds Icmay be prepared from the corresponding compound Ic in which M ishydrogen in a known manner involving the reaction of a compound Ic inwhich M is hydrogen with a strong base such as an alkali metal hydrideor alkoxide, preferably sodium hydride. The reaction is convenientlyeffected at from 0°C. to 50°C., preferably at about room temperature, inan inert solvent which can be employed as solvent for the reaction ofStep B. The conversion of the metallo substituted pyrimidinone of theformula Ic to the desired product may be carried out at temperatures offrom 0°C. to 100°C., preferably 10°C. to 40°C. and conveniently at roomtemperature. When the Step B reaction is carried out with a compound Icin which M is hydrogen, the reaction is conducted in the presence of astrong base, e.g., sodium hydride. In either case, the conditions oftime, temperature and quantity of strong base and compound V aregenerally controlled based on the premise that the alkylation oralkenylation of Step B will favor the 3- position of the compound of theformula Ic. For example, when employing a compound of the formula Ic inwhich R₂ " is hydrogen, the more controlled or limited conditions wouldfavor the production of the compound of the formula Ib in which R₂ ishydrogen. On the other hand, increased quantities of the strong base andalkylating or alkenylating agent and the longer reaction times andhigher temperatures will result in increased quantities of the compoundof the formula Ib in which R₂ and and R₃ " are similar alkyl or alkenylgroups. Since the compounds of the formula I in which R₂ and R₃ aresimilar are very conveniently prepared by the Step A reaction, it willbe evident that the reaction of Step B should merit seriousconsideration only when producing final products in which R₃ is ahydrocarbon group and R₂ and R₃ are dissimilar.

The reaction of Step C and the preparation of the intermediate of theformula Ie in which M is an alkali from a compound Ie in which M ishydrogen is carried out analogously to the reaction of Step B. It willbe evident from the foregoing that Step C should also only merit seriousconsideration when producing compounds of the formula Id in which R₂ '"and R₃ " are dissimilar hydrocarbon groups.

The preparation of compounds of the formula Ia by the reaction of Step Dmay be carried out by heating a compound of the formula VII at elevatedtemperatures preferably in the range of 120°C. to 200°C., morepreferably 130°C. to 180°C. and desirably in the presence of an inertsolvent and strong base. The inert solvents may be of conventional typeand are preferably the higher boiling solvants, e.g., diglyme. Suitablestrong bases include the strong inorganic bases such as the alkali metalhydroxides, e.g. sodium hydroxide. Reaction time may vary, particularlywith temperature, with good results usually obtained in one-half to tenhours.

The compounds of the formula VII employed in Step D may be prepared byreacting a compound of the formula III with a compound of the formula IVunder controlled temperature and time conditions. In general,temperatures are usually in the range of from 20°C. to 120°C.,preferably 60°C. to 115°C. Reaction times may be typically of the orderof from 10 minutes to 5 hours and generally will vary inversely withreaction temperature. The reaction is preferably carried out in thepresence of a base such as an inorganic base, e.g., potassium carbonate,and in the presence of an inert solvent of conventional tupe. Thesolvents boiling at reflux temperatures are generally preferred, e.g.,benzene and toluene. The resulting product of the formula VII may, ifdesired, be isolated and recovered by working up by conventionalprocedures.

It will be evident that the compounds of the formula VII in which R₃ 'is hydrogen exist in and be expressed by the alternative and equivalenttautomeric form having the formula VIIA: ##SPC11##

in which R, R₁ and R₂ ' are as defined.

The compounds of the formulae III, IV, V and VI are either known or maybe produced from known materials by established procedures.

The compound of the formula I in which both R₂ and R₃ are hydrogen formacid addition salts and the pharmaceutically acceptable acid additionsalts not materially depreciating the pharmacological effect of saidcompounds are included within the scope of the compounds of the formulaI of the invention. Such salts include the well known pharmaceuticallyacceptable salts, e.g., the hydrochloride, maleate, etc. The acidaddition salts may be produced from the corresponding free base byconventional procedures. Conversely, the free bases may be obtained fromthe salts by procedures known in the art.

The compounds of formula I of the invention are useful because theypossess biological activity. In particular, the compounds of the formulaI are useful as agents for relieving the symptomatic effects of therelease of histamine, i.e., as anti-histaminic agents, as indicated byobserving the respiratory status on oral administration (5-100mgs./kgs.) to the unanesthetized guinea pig exposed to aerosolizedhistamine dihydrochloride according to a modification of the method ofVan Arman et al., J. Pharmacol, Exptl. Therap. 133: 90-97, 1961. Forsuch use and depending upon known variables satisfactory results areobtained in general on the daily administration of from 1 to 100milligrams per kilogram of body weight, preferably given in divideddoses to 2 to 4 times a day, or in sustained release form. For mostmammals the administration of from 60 to 2000 milligrams per dayprovides satisfactory results and dosage forms suitable for internaladministration comprise 15 to 1000 milligrams of the compound inadmixture with a solid or liquid pharmaceutical carrier or diluent.

The preferred compounds of the invention from the standpoint ofanti-histaminic activity are those in which R₁ is benzyl includingsubstituted benzyl, particularly unsubstituted benzyl or halobenzyl,e.g. fluorobenzyl, especially 4-halobenzyl, and the more preferredcompounds are those in which R is hydrogen and/or R₂ is alkyl, morepreferably of 1 to 3 carbon atoms and more preferably with R₃ beinghydrogen.

For the use indicated above, the compounds may be combined with apharmaceutically acceptable carrier, and such other conventionaladjuvants as may be necessary, and administered orally or parenterally.For most uses oral administration with carriers is preferred and maytake place in such conventional forms as tablets, dispersible powders,granules, capsules, suspensions, syrups and elixirs. Such compositionsmay be prepared according to any method known in the art for themanufacture of pharmaceutical compositions, and such compositions maycontain one or more conventional adjuvants, such as sweetening agents,flavoring agents, coloring agents and preserving agents, in order toprovide an elegant and palatable preparation. Tablets may contain theactive ingredient in admixture with conventional pharmaceuticalexcipients, e.g., inert diluents such as calcium carbonate, sodiumcarbonate, lactose and talc, granulating and disintegrating agents,e.g., starch and alginic acid, binding agents, e.g., starch, gelatin andacacia, and lubricating agents, e.g., magnesium stearate, stearic acidand talc. The tablets may be uncoated or coated by known techniques todelay disintegration and adsorption in the gastro-intestinal tract andthereby provide a sustained action over a longer period. Similarly,suspensions, syrups and elixirs may contain the active ingredient inadmixture with any of the conventional excipients utilized for thepreparation of such compositions, e.g., suspending agents(methylcellulose, tragacanth and sodium alginate), wetting agents(lecithin, polyoxyethylene stearate and polyoxyethylene sorbitanmonooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules maycontain the active ingredient alone or admixed with an inert soliddiluent, e.g., calcium carbonate, calcium phosphate and kaolin. Thepreferred pharmaceutical compositions from the standpoint of preparationand ease of oral administration are solid compositions, particularlyhard-filled capsules and tablets. Parenteral administration may be insuch conventional forms as injectionable solutions and suspensions.

A representative formulation is a tablet for oral administration 2 to 4times a day for relieving the effects of histamine release and preparedby conventional tabletting techniques to contain the followingingredients:

    Ingredients          Weight (mg.)                                             ______________________________________                                        1-(4'-fluorobenzyl)-2-methylamino-                                            pyrido[2,3-d] pyrimidin-4(1H)-one                                                                  25                                                       Tragacanth           10                                                       Lactose              222.5                                                    Corn Starch          25                                                       Talcum               15                                                       Magnesium Stearate   2.5                                                      ______________________________________                                    

It will be evident to those skilled in the art that the compounds of theformula I in which R₃ is hydrogen are tautomeric and have thealternative and equivalent structure represented by the formula IA:##SPC12##

wherein R, R₁ and R₂ are as defined.

The following examples show representative compounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However, it is to be understood that the examples are forpurposes of illustration only.

EXAMPLE 1 1-(4'-fluorobenzyl)-2-methylamino-pyrido[2,3-d]pyrimidin-4(1H)-one. ##SPC13##

A mixture of 25 g. of4-(4'-fluorobenzyl)-3,4-dihydro-1,3-dioxo-1H-pyrido[2,3-d] [1,3]oxazine,15 g. of S,N-dimethyl-thiopseudourea (hydrogen iodide), 15 g. ofanhydrous potassium carbonate and 300 ml. of diglyme is refluxed withstirring for 4 hours. The resulting mixture is filtered while hotthrough Celite and the precipitate formed on cooling is recovered byfiltering, washed with diglyme and then three times with either and thendried under reduced pressure. The resulting product is dissolved inmethylene chloride/methanol, filtered to remove insoluble material,concentrated on a steam bath and treated with ether to crystallize thetitled produce (free base form), m.p. 242-246°C.

EXAMPLE 2

Following the procedure of Example 1 the following compounds of theinvention are prepared:

a. 1-ethyl-2-methylamino-pyrido[2,3-d]pyrimidin-4(1H)-one, m.p.275°-280°C.

b.1-(4'-fluorobenzyl)-2-methylamino-3-methyl-2,3-dihydro-pyrido[2,3-d]pyrimidin-4(1H)-one,m.p. 112°-114°C.

c. 1-(4'-fluorobenzyl)-2-ethylamino-pyrido[2,3-d]pyrimidin-4(1H)-one,m.p. 249°-253°C.

d. 1-(4'-fluorobenzyl)-2-methylamino-7-methyl-pyrido[2,3-d]pyrimidin-4(1H)-one.

EXAMPLE 3 1-(4'-fluorobenzyl)-2,3-dihydro-2-imino-3-methyl-pyrido[2,3-d]pyrimidin-4(1H)-one. ##SPC14##

To a suspension of 0.4 g. of sodium hydride in 60 ml. ofdimethylacetamide is added 2.5 g. of1-(4'-fluorobenzyl)-2-amino-pyrido[2,3-d]pyrimidin-4(1H)-one whilemaintaining the system under nitrogen. After stirring for one hour atroom temperature, the mixture is treated by addition of 1.0 ml. ofmethyliodide. The resulting mixture is stirred at 20°C. for 15 hours. Asmall amount of water (ca 1.0 ml.) is then added and the mixtureevaporated in vacuo. The residue is treated with ice/water and theresulting precipitate is recovered by filtering, washed with water anddried. The dried precipitate is then dissolved in methylene chloride,treated with charcoal and filtered through neutral alumina. The filtrateis concentrated in vacuo and ether added to obtain on crystallization1-(4'-fluorobenzyl)-2,3-dihydro-2-imino-3-methyl-pyrido[2,3-d]pyrimidin-4(1H)-one

EXAMPLE 4 Alternate Process for1-(4'-fluorobenzyl)-2-methylamino-pyrido[2,3-d]pyrimidin-4(1H)-one.

STEP A: Preparation of S,3-dimethyl-1-[2-(4'-fluorobenzyl)amino]nicotinoyl thiourea ##SPC15##

A mixture of 10 g. of4-(4'-fluorobenzyl)-3,4-dihydro-1,3-dioxo-1H-pyrido[2,3-d][1,3]oxazine,9.5 g. of S,N-dimethyl-thiopseudourea (hydrogen iodide), 6 g. ofanhydrous potassium carbonate and 200 ml. of toluene is refluxed withstirring for 31/2 hours. The resulting mixture is evaporated to dryness,dissolved in methylene chloride, filtered and extracted twice with icecold 0.5 N hydrochloric acid. The organic phase is washed with water,treated with charcoal, dried, filtered through Celite, evaporated todryness and chromatographed over silica gel using methylene chloride asthe eluant. The head fractions contain a small amount of startingmaterial. The further elutions are combined, evaporated and the residuecombined with ether followed by cooling to obtain with scratching aprecipitate which is recovered by filtering, washed with ice cold etherand dried under high vacuum to obtainS,3-dimethyl-1-[2-(4'-fluorobenzyl)amino]nicotinoyl thiourea, m.p.84°-85°C.

STEP B: Preparation of 1-(4'-fluorobenzyl)-2-methylamino-pyrido[2,3-d]pyrimidin-4(1H)-one.

A mixture of 1.7 g. ofS,3-dimethyl-1-[2-(4'-fluoro-benzyl)amino]nicotinoyl thiourea, 0.5 g. ofsodium hydroxide and 40 ml. of diglyme is refluxed for 3 hours and theresulting reaction mixture worked up in a manner similar to Example 1 toobtain1-(4'-fluorobenzyl)-2-methylamino-pyrido[2,3-d]pyrimidin4(1H)-one, m.p.242°-247°C.

EXAMPLE 51-(4'-fluorobenzyl)-2-allylamino-pyrido[2,3-d]pyrimidin-4(1H)-one.##SPC16##

A mixture of 27 g. of4-(4'-fluorobenzyl)-3,4-dihydro-1,3-dioxo-1H-pyrido[ 2,3-d] [1,3]oxazine, 27.5 g. of S-methyl-N-allylthiopseudourea (hydrogen iodide), 12g. of anhydrous sodium carbonate and 250 ml. of acetonitrile is refluxedwith stirring for one hour. The resulting mixture is evaporated todryness, the residue dissolved in methylene chloride filtered throughcelite and the filtrate evaporated in vacuo to obtain an oil ofS-methyl-3-allyl-1-[2-(4'-fluorobenzyl) amino]nicotinoyl thiourea. Thisoil is dissolved in 150 ml. of diglyme and refluxed for 1.5 hours. Theresulting reaction mixture is cooled and the resulting crystallinematerial is recovered by filtering, washed with diglyme and then twicewith ether, dried in a high vacuum, dissolved in methylenechloride/methanol, filtered, concentrated on a steam bath and etheradded to obtain 1-(4'-fluorobenzyl)-2-allylamino-pyrido 2,3-dpyrimidin-4(1H)-one, m.p. 190-194°C. 190°-

What is claimed is:
 1. A compound of the formula ##SPC17##wherein R₁ isalkyl of 1 to 6 carbon atoms, alkenyl of 3 to 8 carbon atoms orphenalkyl of the formula: ##SPC18## n is 0 or 1, R" is hydrogen ormethyl provided that R" is hydrogen when n is 1, R₂ is hydrogen, alkylof 1 to 6 carbon atoms or alkenyl of 3 to 6 carbon atoms, R₃ ishydrogen, alkyl of 1 to 6 carbon atoms or alkenyl of 3 to 6 carbonatoms, R is hydrogen or alkyl of 1 to 3 carbon atoms, and Y and Y' areindependently hydrogen, fluoro, chloro, alkyl of 1 to 3 carbon atoms oralkoxy of 1 to 3 carbon atoms or one is hydrogen and the other bromo ortrifluoromethyl, or a pharmaceutically acceptable acid addition salt ofthe compounds in which each of R₂ and R₃ is hydrogen.
 2. A compound ofclaim 1 in which R₃ is hydrogen.
 3. A compound of claim 1 in which eachof R₂ and R₃ is hydrogen.
 4. A compound of claim 1 in which each of R₂and R₃ is alkyl.
 5. A compound of claim 2 in which R₂ is alkyl.
 6. Acompound of claim 5 in which R₂ is alkyl of 1 to 3 carbon atoms.
 7. Acompound of claim 1 in which R₁ is ##SPC19##
 8. A compound of claim 7 inwhich R" is hydrogen, n is O, Y is hydrogen, fluoro, chloro or bromo andY' is hydrogen, fluoro or chloro, with the proviso that Y' is hydrogenwhen Y is bromo.
 9. A compound of claim 8 in which Y is 4-fluorobenzyl,4-chlorobenzyl or 4-bromobenzyl and Y' is hydrogen.
 10. A compound ofclaim 8 in which R₂ is hydrogen or alkyl and R₃ is hydrogen.
 11. Acompound of claim 10 in which R is hydrogen.
 12. The compound of claim11 which is1-(4'-fluorobenzyl-2-methylimino-pyrido[2,3-d]pyrimidin-4(1H)-one. 13.The compound of claim 6 which is1-(4'-fluorobenzyl)-2-ethylamino-pyrido[2,3-d]pyrimidin-4(1H)-one.
 14. Acompound of claim 1 in which R₁ is alkyl.
 15. A compound of claim 1 inwhich R₂ and R₃ are hydrogen or alkyl.